The desmoplastic reaction surrounding hepatic colorectal adenocarcinoma metastases aids tumor growth and survival via alphav integrin ligation.
OBJECTIVE
The treatment of metastatic colorectal carcinoma represents a major clinical challenge. We investigated the hypothesis that the desmoplastic reaction within the liver elicited by metastatic adenocarcinoma, characterized by collagen I deposition and altered collagen IV distribution, promotes the growth and survival of hepatic colorectal carcinoma metastases.


METHODS
Partial hepatectomy specimens for metastatic colorectal adenocarcinoma were examined immunohistochemically for differential integrin expression. Human colorectal adenocarcinoma cell lines HT-29, KM12SM, and KM12c were grown on wild-type collagen I or IV, or cleavage-resistant r/r collagen I, and assessed for their growth, survival, and resistance to 5-fluorouracil. The effect of alpha(v)beta(3) and alpha(v)beta(5) integrin blockade by neutralizing antibodies was examined.


RESULTS
Collagen I, in contrast to collagen IV, significantly enhanced the growth, survival, and chemoresistance of colorectal carcinoma cells. Blockade of the alpha(v)beta(3) and alpha(v)beta(5) integrins significantly reduced colorectal carcinoma cell proliferation on collagen, especially in the cell line with the most metastatic potential. These in vitro findings correlated with the pattern of integrin expression identified within resected hepatic colorectal carcinoma metastases. Using matrix metalloproteinase-resistant r/r collagen I as a dominant negative ligand for alpha(v) integrins, we showed a key role for this integrin-ligand interaction in mediating the survival and proliferation of colorectal carcinoma cells.


CONCLUSIONS
Desmoplasia has an important role in the development of hepatic colorectal carcinoma metastasis. The interaction between integrin and collagen I is identified as a potential therapeutic target.
Conti
John A
JA
Liver and Pancreas Research Group, University of Southampton, UK. jaconti1@soton.ac.uk
Kendall
Timothy J
TJ
Bateman
Adrian
A
Armstrong
Thomas A
TA
Papa-Adams
Andrew
A
Xu
Qian
Q
Packham
Graham
G
Primrose
John N
JN
Benyon
R Christopher
RC
Iredale
John P
JP
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006498:Hepatectomy; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D039564:Integrin alphaV / Q000276:immunology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D024042:Collagen Type I; D024141:Collagen Type IV; D039564:Integrin alphaV; D005472:Fluorouracil